The Connectome Debate: Is Mapping the Mind of a Worm Worth It?

In the 1970s biologist Sydney Brenner and his colleagues began preserving tiny hermaphroditic roundworms known as Caenorhabditis elegans in agar and osmium fixative, slicing up their bodies like pepperoni and photographing their cells through a powerful electron microscope. The goal was to create a wiring diagram—a map of all 302 neurons in the C. elegans nervous system as well as all the 7,000 connections, or synapses, between those neurons. In 1986 the scientists published a near complete draft of the diagram. More than 20 years later, Dmitri Chklovskii of Janelia Farm Research Campus and his collaborators published an even more comprehensive version. Today, scientists call such diagrams "connectomes."

So far, C. elegans is the only organism that boasts a complete connectome. Researchers are also working on connectomes for the fruit fly nervous system and the mouse brain. In recent years some neuroscientists have proposed creating a connectome for the entire human brain—or at least big chunks of it. Perhaps the most famous proponent of connectomics is Sebastian Seung of the Massachusetts Institute of Technology, whose impressive credentials, TED talk, popular book, charisma and distinctive fashion sense (he is known to wear gold sneakers) have made him a veritable neuroscience rock star.

Other neuroscientists think that connectomics at such a large scale—the human brain contains around 86 billion neurons and 100 trillion synapses—is not the best use of limited resources. It would take far too long to produce such a massive map, they argue, and, even if we had one, we would not really know how to interpret it. To bolster their argument, some critics point out that the C. elegans connectome has not provided many insights into the worm's behavior. In a debate* with Seung at Columbia University earlier this year, Anthony Movshon of New York University said, "I think it's fair to say…that our understanding of the worm has not been materially enhanced by having that connectome available to us. We don't have a comprehensive model of how the worm's nervous system actually produces the behaviors. What we have is a sort of a bed on which we can build experiments—and many people have built many elegant experiments on that bed. But that connectome by itself has not explained anything."

Because a lone connectome is a snapshot of pathways through which information might flow in an incredibly dynamic organ, it cannot reveal how neurons behave in real time, nor does it account for the many mysterious ways that neurons regulate one another's behavior. Without such maps, however, scientists cannot thoroughly understand how the brain processes information at the level of the circuit. In combination with other tools, the C. elegans connectome has in fact taught scientists a lot about the worm's behavior; partial connectomes that researchers have established in the crustacean nervous system have been similarly helpful. Scientists are also learning how to make connectomes faster than before and to enhance the information they provide. Many researchers in the field summarize their philosophy like this: "A connectome is necessary, but not sufficient."

"Some people say we don't know anything about how C. elegans's brain works and I am like, 'Yes, we do!'" says Cornelia Bargmann of The Rockefeller University, who has studied the nematode for more than two decades and attended the Columbia debate. "A lot of what we know about C elegans's rapid behaviors we have learned through and with the connectome. Every time we do an experiment, we look at those wiring diagrams and use them as a starting point for generating hypotheses."

Early birds
As soon as Brenner and his colleagues at the University of Cambridge completed the 1986 draft of the C. elegans connectome, a few things became clear. First, scientists were able to label every one of the 302 neurons as either a sensory neuron (one that collects information from the environment, such as temperature or pressure); a motor neuron that controls muscles; or an interneuron, which connects the two. Scientists had already identified some neurons as motor or sensory by destroying them with lasers and observing what abilities the worm lost or retained. With the connectome, they could categorize all of C. elegans's neurons by referencing the number and types of connections between them. On average, sensory neurons make more presynaptic connections (sites where neurons spit out chemical messages) and fewer postsynaptic connections (where neurons receive chemical messages) because sensory neurons are mainly in the business of sending information to other cells. Motor neurons show the inverse trend. Each type of neuron constituted about one third of the C. elegans nervous system. The wiring diagram also allowed scientists to immediately identify how a neuron of interest was linked to other neurons. If a researcher zapped a neuron near the worm's head and discovered that the nematode no longer inched toward food, he could look up that neuron in the connectome and see exactly how it was connected to motor neurons.

In the 1980s, as a postdoctoral student in Brenner's lab, Martin Chalfie—now at Columbia University—used the C. elegans wiring diagram to explain one of the worm's behaviors: He identified the specific neural circuits responsible for the worm's tendency to wriggle backward when poked on the head and to squirm forward when touched on the tail. "The connectome was absolutely critical," Chalfie says. "Without it, we simply would not have known which cells were connected to which." By combining the wiring diagram with evidence from previous research, Chalfie predicted that a particular set of interneurons mediated forward movement and that another was involved in backward movement. Annihilating those neurons with lasers confirmed his predictions.

Although the C. elegans connectome has been a boon for scientists who study this nematode's behavior, the past two decades of research have also underscored the staggering intricacy of even a relatively small nervous system. "When you move onto behaviors that are more complex than a quick reflex, you're dealing with especially complicated pathways that are not immediately interpretable because they are not simple circuits—they are networks," explains Scott Emmons of Albert Einstein College of Medicine.

This past summer, in an attempt to confront some of that complexity, Emmons and his colleagues published a connectome of the male nematode's tail, which contains most of the 81 extra neurons that distinguish it from the hermaphrodite (giving the male a total of 383 neurons). It took Emmons and his team about three years to complete and publish the partial connectome: he used more or less the same techniques that Brenner relied on in the 1970s, albeit with faster computers, more powerful microscopes and digital cameras. The male C. elegans connectome also features a crucial piece of information missing from the original draft of its counterpart: synaptic weights. The many connections between neurons are not equal in strength—the more two neurons communicate, the stronger their link becomes and the more likely one is to fire when the other fires. Neurons may also be genetically programmed to form stronger connections with certain partners as the nervous system develops.

Analyzing synaptic weights in the male nematode's connectome has already given Emmons some ideas about neural development. Some neuroscientists have proposed that genes tightly regulate the strongest connections between neurons in C. elegans, whereas weaker connections are more or less accidents—neurons hooking up with whomever they bump into. Emmons's preliminary analysis shows that homologous pairs of neurons on either side of the nematode's body form highly similar strong and weak connections, suggesting that even the weak connections are not entirely random.

Dynamic networks
Synaptic weights are just one of the many layers of information missing from typical connectomes. To understand how neural circuits work, one also needs to know whether the relevant neurons are excitatory—increasing the likelihood that linked cells fire—or inhibitory, muffling their partners instead. Further complicating things, neglected neurons shrivel in the developing brain and new neurons sprout to replace them; in the adult brain, neurons change the strength of their connections with one another daily—such flexibility is essential for learning and memory. Yet another level of complexity involves neuromodulators: certain kinds of neurotransmitters and other small molecules that linger in the fluid surrounding neurons, changing how neurons behave in ways we do not yet fully understand. A prediction about how information will flow through a particular circuit based on a wiring diagram and synaptic weights might be completely wrong if one does not know which neuromodulators are hanging around at any given time.

A good example of how a static connectome fails to capture the dynamics of living neural networks comes from research on the stomatogastric ganglion (STG), a pair of neural circuits in crustaceans—including crayfish, crabs, lobsters and shrimp—that generate rhythmic behavior in response to food. One subcircuit repeatedly constricts and dilates the pyloric region of the stomach, the foyer to the small intestines. Another subcircuit pulsates the gastric mill, a muscular pouch lined with chitinous teeth that help break down food. Mapping all the connections between the 30 neurons in the crustacean STG was an important first step toward understanding how the STG controlled the crustacean digestive system. But it was by no means sufficient. Eve Marder of Brandeis University and others have shown that the neurons in the stomatogastric ganglion do not always use the same unchanging set of connections to communicate with one another. In the presence of certain neuromodulators, a neuron that contributes to the pyloric subcircuit might switch teams, joining the gastric mill subcircuit instead by changing the tempo at which it fires.

Because any brain or nervous system is so much more complex than what a connectome by itself represents, Movshon is certainly not alone in thinking that researchers' limited resources are better devoted to other areas of neuroscience. "I'm all in favor of Seung and others," Bargmann says, "but I don't think we should have a Manhattan Project for the connectome with such a huge amount of resources. We are not quite good enough at reading them. It wasn't like the human genome project, where we knew how to sequence DNA and said, 'Yeah, let's go for it!' Scaling up connectomes is a different issue."

Oliver Hobert of Columbia, another longtime C. elegans researcher, agrees that connectomics only scratches the surface. "It's like a road map that tells you where cars can drive, but does not tell you when or where cars are actually driving," he says. "Still, connectomics of C. elegans has given us wonderful testable hypotheses in terms of how neural circuits work. What we have learned from C. elegans diagrams are not just specific worm behaviors—they are logical principles common to much of biology."

*Editor's Note: The author is a member of NeuWrite, a workshop of scientists and writers that organized the debate at Columbia.